Vitamin D in a Nutshell

Başak Gökçe ÇÖL*, Eda Merve KURTULUŞ**, Fuzail Mohammed MAJOO***

Abstract

This review comprises the synthesis, function, measurement and also the recommendations of Vitamin D and its derivates. In light of the evidence provided by clinical trials, deficient vitamin D levels were found to be correlated with higher incidences of rickets, skeletal disorders, diabetes, obesity, cardio vascular disorders, asthma, depression, schizophrenia and immune disorders. Vitamin D supplementation which is available at low cost and with a wide therapeutic window, should be implemented to the population and should be monitored only in patients with a high risk of kidney and liver diseases, hyperparathyroidism, sarcoidosis, tuberculosis and histoplasmosis. Keywords: Vitamin D function, Vitamin D deficiency, Vitamin D sources

Kısaca D Vitamini

Öz

Bu derleme D Vitamini ve türevlerinin sentezi, fonksiyonu, ölçümü ve önerilen D vitamin kullanım dozlarını incelemektedir. Klinik deney bulgularının ışığı altında D vitamin eksikliği raşitizm, kas-kemik bozuklukları, diyabet, obezite, kardiyo vasküler bozukluklar, astım, depreseyon, şizofreni ve bağışıklık sistemi bozuklukları ile alakalı bulunmuştur. D vitamini takviyeleri düşük maliyetli olup odukça geniş bir terapötik alan etkinliğine sahip

Derleme Makale (Review Article) Geliş Tarihi: 20.02.2017 Kabul Tarihi: 04.04.2017 * Assist. Prof. Dr., Istanbul Gelisim University, Nutrition and Dietetics Department, Istanbul, Turkey, E-mail: [email protected] ** Lecturer, Istanbul Gelisim University, Nutrition and Dietetics Department, Istanbul, Turkey, E-mail: [email protected] *** Lecturer, Istanbul Gelisim University, Nutrition and Dietetics Department, Istanbul, Turkey, E-mail: [email protected]

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olduğundan toplumca kullanımı özendirilmelidir. D vitamini kullanımına bağlı gelişebilecek toksitite ve yan etkilerin önüne geçilmesi için doz takibinin karaciğer ve böbrek hastalıkları açısından riskli gruplarda ve hiperparatiroidizm, sarkoidoz, tüberküloz ve histoplazmoliz durumlarında yapılması etkili ve yeterlidir. Anahtar Sözcükler: D Vitamini işlevi, D Vitamini eksikliği, D Vitamini kaynakları

Introduction

Types of Vitamin D and Their Synthesis

The fat-soluble vitamin D can be categorized into 5 subclasses (D2-D5) due to its structural types and sources. Though the active form found in the human body is

D3, vitamin D is generally used to describe both D3 and D2 in the literature.

Vitamin D5, also known as sitocalciferol, derived from 7-dehydrositosterol, is the least toxic form of artificially produced form of D3. On the other hand, D4, also known as 22, 23-hydroergocalciferol with a methyl group in the side chain is originated from mushrooms. Vitamin D2, also known as ergocalciferol, is a secosteroid form of cholesterol produced by algae, yeasts, plants, fungus and invertebrates. Vitamin D2 differs from D3 not only by the nutritional sources, but also by its structural properties as D2 which has a double bond between C22 and

1 C23 and a methyl group at C24 in the side chain . D2 also has a closed formula of

C28H44O. On the other hand Vitamin D3, which is also known as cholecalciferol, has a closed formula of C27H44O. Vitamin D3 is derived from animal based sources such as cod liver oil, fish oil, fish roe, beef and dairy

2 products . Aside from its nutritional diversity, D3 has dermal synthesis from 7- dehydrocholesterol which is a derivate of cholesterol. Exposure to sunlight at the 290–315 nm UVB range, results in the high-energy photons to be absorbed in the conjugated 6,7-diene in the B-ring of ergosterol and 7-dehydrocholesterol, resulting in the ring being opened at C9 and C10 with the formation of pre vitamin D3. From the site of synthesis in the epidermis, pre vitamin D diffuses through the blood with 85% of it carried to the liver by a specific transport protein, called vitamin D binding protein (DPB)4. The remaining 15% of the vitamin D is carried by albumin. Even though the mass content of vitamin D shows high affinity to

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albumin, polyunsaturated fatty acid content of albumin can decrease this

5 attraction . It was also shown that differences between D3 and D2 in their side chains, affect their affinities in DBP binding in favor of D3. Thus D2 shows a faster clearance from circulation, and a limited conversion, whereas the side chains

6 feature an increased stability, thus altering catabolism and clearance to D3 . In this stage, D2 and D3 are considered to be prohormones with no activity other than pre-vitamins. Their active forms require a 3 step enzymatic reaction6 that initiates in liver. The 25-hydroxylase enzyme, which is found in both microsomal and mitochondrial fractions, sorely CYP27A1, is a mitochondrial enzyme, which only functions in the hydroxylation of D3.

CYP2R1, identified in the microsomal fraction, carries out hydroxylation and

1 produces 25-hydroxylates of both D2 and D3 . Prohormones of 25(OH)D3 and

25(OH)D2 are transported from the liver to the kidneys via circulation mainly by D vitamin Binding Protein (DBP), also known as group specific component (GC), a hepatocytes originated protein7 and by other lipophilic proteins such as specific globulins (ex: albumin). Even though these steroid hormones can diffuse through the cellular membrane of kidneys, receptor mediated endocytosis protein called megalin facilities the uptaking process by reabsorbing the vitamin and its ligand from the proximal tubules surface to luminal sites8,9. In the mitochondria of the epithelial cells found in proximal tubules of the liver; by the reactions of 1α- hydroxylation or 24-hydroxylation of cytochrome P450 mixed-function oxidase enzymes, either the active form, 1,25 dehydroxycholecalciferol or relatively inactive form of the vitamin as 24, 25 dehydroxyvitamin are generated9.

Seasonal Changes Effects on Vitamin D Synthesis

As our knowledge of vitamin D synthesis increases, the aspects for regulating vitamin D levels vary. One method for increasing vitamin D is through sun exposure. Studies show that inadequate exposure to the sun and Vitamin D intake, can cause vitamin D insufficiency, while the conversion of 7- dehydrocholesterol to previtamin D3 is limited to 15% in the skin. In an Australian study, it has been showed that only 3.9% of the difference in vitamin

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levels depend on the lattitute10. Not only the 290 to 315 nm length of the UVB, but also the zenith angel (The angle formed between the sun's rays and the horizontal surface) of the sun affect the rate of synthesis. Generally, in higher latitudes then 33° and shorter distances from the equator, less UVB reaches the cutaneous naked skin, leading to less Vitamin D synthesis. While there is no absorption for all kinds of UVB radiation through glass, it should be kept in mind that as long as

UVB has no direct contact with bare and naked skin, vitamin D3 will not be produced11. Studies in the North (34 degrees N and 18 degrees N) populations, display that vitamin D synthesis occurs during 6 months of the year, from November through February12,13. In Turkey, with 39°N Latitude and 35°E Longitude, research show that Vitamin D synthesis is only possible during April to November. This eight-month long illumination cannot prevent Vitamin D insufficiency. Throughout the year 59% of the population is shown to have insufficiency with a level of 13.9µ/l in general and 19.7 μ/l in the summer season. The rate reaches to 94% during the winter period14.

Measurements of Vitamin D Levels

Measurements of 25(OH) D levels are essential for clinically evaluating the disorders related to bone diseases and the health status of patients. In the early

70s, an assay measuring both the 25(OH)D2 and 25(OH)D3 through competitive binding of DBP was introduced by another assay technique; sialic acid chromatography15. In late 70s, High Performance Liquid Chromatography assays (HPLC) using UV absorption assay was developed16. Because eliminating the interfering lipid molecules and D vitamin derived metabolites required advanced technology, search for alternative methods continue. Even though RIA (Diasorin) which requires no pre-analytic elimination has been in use since the late 80s, HPLC assays are considered to be the gold standard. Liquid Chromatography combined with Mass spectrometry (LC-MS/MS) are also being used in reference laboratories with a trend revealing a switch in favor of LC-MS16. In a study comparing the standard deviations of the techniques of Immunoassays DiaSorin Liaison, IDS ISYS, Abbott Architect and the Siemens ADVIA Centaur suggest that both methods show accordance17.

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In order to compare and validate the levels of Vitamin D2 and D3 pre analytical studies are also carried for sampling types, amounts, centrifugation and storage conditions. The results showed that the stability of Vitamin D was unchanged up to 4 hours at room temperature or 24 hours at 2-8° C. At lower temperatures, Vitamin D was unchanged or slightly unchanged (up to a 10% decrease in the level) being stored at -20° C for 24 hours, 7 days or at -80°C for 3 months18,19.

Sources of Vitamin D

Even though the synthesis of Vitamin D is common in animals and plants, the sufficient amount contained in daily food types are limited. The main animal sources of vitamin D can be listed as; fatty fish (salmon, tuna, sardines, mackeral) and fish liver oil. In the study of Mattila et al. even though the highest content of

D3 was found in liver of beef meat, the content was not greater than 0.0–9.0 μg/kg20. Following meat, dairy products such as eggs and offal can also be included, even though their content is not as high as seafood21. The level of Vitamin D can be elevated by exposure to UV light in plants and fungi as well.

Some plants and fungi (eg. mushrooms) may include Vitamin D2 naturally.

Foods fortified with Vitamin D3 such as dairy products, have been in use in several countries. Vitamin D supplemented foods are added voluntary in USA and United Arab Emirates or by law in Canada2. When compared, nearly all milk consumed in the USA is fortified with 100IU of vitamin D per cup, whereas the fortification amount of milk in Canada is limited to 35–40 IU/100 mL. Margarine, cheese, yogurt, crema, orange juice and cereals are other samples of fortified products.

Functions and Importance of Vitamin D

Calciferol, the other name of the active 1,25 dehydroxycholecalciferol prohormone, through electro-chemical gradient regulated channels and by upregulating the expression of calcium binding proteins in the brush membrane borders of intestine, plays a role in calcium uptake. In a similar manner,

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phosphorus absorption in the ileum is regulated. Vitamin D receptors, by upregulating the expression of receptor activator of nuclear factor kB ligand, (RANKL) controls the turnover rate of osteoclasts15. In the kidneys, vitamin D prevents calcium loss while in bones, up regulates calcium resorption. In the parathyroid glands, vitamin D inhibits parathyroid hormone synthesis and release, which plays a role in the preventation of rickets and osteomalcia1. Epidemiologic evidence suggest that vitamin D and its analogs suppresses tumor development especially in the colon and breasts. Vitamin D receptors can be found in the tissues of organs such as the brain, prostate, and muscle 21, A lack of Vitamin D is found to correlate with cardiovascular, immune diseases, schizophrenia, obesity and diabetes22.

Vitamin D Deficiency, Prevention and Treatment

Globally, Vitamin D deficiency is currently implicated as an epidemic in both adults and pediatrics23. According to surveys in the USA, Canada and European countries, Vitamin D deficiency occurs at a rate of 30 to 50% 24. In England, one study has shown over 50% of the population has Vitamın D deficiency, of which 16% has insuffıcıent levels. In another study in Ankara, Turkey, Vitamin D deficiency was observed in 51.8% of the population of which 20.7% were found to be insufficient25 . The two main causes of Vitamin D deficiency are due both to a lack of sun exposure, and inadequate intake of foods containing vitamin D. Fortified foods with vitamin D and supplements play an important role in the prevention and treatment of Vitamin D deficiency/insufficiency.

Many studies have been carried out to show Vitamin D insufficiency/ deficiency based on the metabolism of calcium and its interactions with serum parathyroid hormone (PTH) and 25 (OH) D levels. Based on the Endocrine Society Clinical Practice Guideline; vitamin D deficiency is determined as serum 25 (OH) D level of <20 ng/ml, and insufficiency to be between 21 and 29 ng/ml. Sufficient levels of 25 (OH) D is >30 ng/ml23.

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Daily Recommendation

The The daily vitamin D intake recommendations according to the Institute of Medicine (IOM) to prevent vitamin D deficiency are as follows: birth to 12 months, 400 IU. 1-70 years 600IU/day and 800 IU/day for age 70 and over 23. However, recommendations from IOM are not sufficient for the Endocrine Society to evaluate serum 25(OH) D level greater than 30 ng/ml. The Endocrine Society Practice guideline recommends the following levels of daily intake for D vitamin supplementation: for the first year in infants 400-1000 IU (up to 2000 IU). Between ages 1-18, 600-1000 IU per day (up to 4000 IU). Over 18 years old, 1500-2000 IU (up to 10,000 IU). In obese individuals, those with malabsorption syndrome, individuals using glucocorticoid or antiepileptic drugs, higher Vitamin D doses may be required. In obese patients, patients with malabsorption syndrome and patients who use medications that affect vitamin D metabolism, high dose vitamin D treatment with at least 6000-10,000 IU / day and maintenance treatment at 3000-6000 IU / day is recommended.

The strategy of administering doses of 50,000 IU D twice monthly could prevent vitamin D deficiency/insufficiency without any toxic effect and recurrences, for up to 6 years.

A recently published study showed that 50,000 IU Vitamin D intake every two weeks or equivalent 3000 IU / day intake in adults, sustain blood levels of 25 (OH) D between 40 and 60 ng / mL without any toxicity 26,27. In Turkey, the prevelance of nutritional rickets is found at a rate of 1.7%-19% in children, with vitamin D3 insufficiancy and as 80.2% in fertile woman. Under the preventation program, the Turkish Ministery of Health has been providing 400IU/daily dose of Vitamin D distrubition to infants from birth to 12 months28.

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Result

Vitamin D applications are low cost and effective therapeutic agents that will be used in the preventation of rickets, obesity and in cardiovascular diseases. To avoid any possible toxicity and side effects that may occur due to the use of vitamin D supplements, it is more effective to perform dose follow-up test only in risky groups in terms of liver and kidney diseases patients of hyperparathyroidism, sarcoidosis, tuberculosis and histoplasmolysis.

REFERENCES

1. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol. 2014;21(3):319-329. doi:10.1016/j.chembiol.2013.12.016. 2. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium Dietary reference intakes for calcium and Vitamin D. National Academies Press (US); 2011. doi:10.17226/13050. 3. Havinga E. Vitamin D, example and challenge. Experientia. 1973;29(10):1181-1193. http://www.ncbi.nlm.nih.gov/pubmed/4758912. Accessed January 26, 2017. 4. Jäpelt RB, Jakobsen J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Front Plant Sci. 2013;4:136. doi:10.3389/fpls.2013.00136. 5. Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M. Vitamin D and DBP: The free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014;144 (PART A):132-137. doi:10.1016/j.jsbmb.2013.09.012. 6. Tripkovic L, Lambert H, Hart K, Smith CP, Bucca G, Penson S, Chope G, Hyppönen E, Berry J, Vieth R, Lanham-New S. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D

66 http://igusabder.gelisim.edu.tr

B. G. ÇÖL, E. M. KURTULUŞ, F. M. MAJOO

IGUSABDER, 1 (2017): 59-69.

status: a systematic review and meta-analysis. Am J Clin Nutr. 2012;95(6):1357-1364. doi:10.3945/ajcn.111.031070. 7. Gressner OA, Lahme B, Gressner AM. Gc-globulin (Vitamin D binding protein) is synthesized and secreted by hepatocytes and internalized by hepatic stellate cells through Ca2+-dependent interaction with the megalin/gp330 receptor. Clin Chim Acta. 2008;390(1-2):28-37. doi:10.1016/j.cca.2007.12.011. 8. Christakos S, Ajibade D V, Dhawan P, Fechner AJ, Mady LJ. Vitamin D: metabolism. Endocrinol Metab Clin North Am. 2010;39(2):243-53, table of contents. doi:10.1016/j.ecl.2010.02.002. 9. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal

uptake and activation of the steroid 25-(oh) vitamin D3. Cell. 1999;96(4):507-515. doi:10.1016/S0092-8674(00)80655-8. 10. Van der Mei I A-F, Ponsonby A-L, Ola Engelsen O, Pasco JA, McGrath JJ, Eyles DW, Blizzard L, Dwyer T, Lucas R, and Jones G. The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude. Environ Health Perspect. 2007;115(8):1132-1139. doi:10.1289/ehp.9937. 11. Hossein - Nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88(7):720-755. doi:10.1016/j.mayocp.2013.05.011. 12. Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol. 2013;5(1):51-108. doi:10.4161/derm.24494. 13. Webb AR, Kline L, Holick MF. Influence of season and latitude on the

cutaneous synthesis of Vitamin D3 : exposure to winter sunlight in boston

and edmonton will not promote Vitamin D3 synthesis in human skin. J Clin Endocrinol Metab. 1988;67(2):373-378. doi:10.1210/jcem-67-2-373. 14. Bozkurt S, Alkan BM, Yıldız F, Gümüş S, Sezer N, Ardıçoğlu Ö, Akkuş S.

Age, sex, and seasonal variations in the serum Vitamin D3 levels in a local Turkish population. Arch Rheumatol. 2014;29(1):14-19. doi:10.5606/tjr.2014.3968. 15. Öngen B, Kabaroğlu C, Parıldar Z. Biochemical and laboratory evaluation of Vitamin D Türk Klinik Biyokimya Derg. 2008; 6(1): 23-31

67

B. G. ÇÖL, E. M. KURTULUŞ, F. M. MAJOO IGUSABDER, 1 (2017): 59-69.

16. Biancuzzo RM, Clarke N, Reitz RE, et al. The measurement of Vitamin D: analytical aspects. Ann Clin Biochem. 2004;41(2):272-281. doi:10.1258/0004563041201464. 17. Koivula MK, Matinlassi N, Laitinen P, Risteli J. Four automated 25-OH total vitamin D immunoassays and commercial liquid chromatography TM spectrometry in Finnish population. Clin Lab. 2013;59(3-4):397- 405.doi:10.7754/Clin.Lab.2012. 120527. 18. Ockè MC, Schrijver J, Obermann-de Boer GL, Bloemberg BP, Haenen GR, Kromhout D. Stability of blood (pro)vitamins during four years of storage at -20 degrees C: consequences for epidemiologic research. J Clin Epidemiol. 1995;48(8):1077-1085. http://www.ncbi.nlm.nih.gov/pubmed/7775995. Accessed February 7, 2017. 19. Colak A, Toprak B, Dogan N, Ustuner F. Effect of sample type, centrifugation and storage conditions on vitamin D concentration. Biochem medica. 2013;23(3):321-325. doi:10.11613/bm.2013.039. 20. Mattila PH, Piironen VI, Uusirauva EJ, Koivistoinen PE. Contents of cholecalciferol, ergocalciferol, and their 25-hydroxylated metabolites in milk-products and raw meat and liver as determined by HPLC. J Agric Food Chem. 1995;43(9):2394-2399. doi:10.1021/jf00057a015. 21. Schmid A, Walther B. Natural vitamin D content in animal products. Adv Nutr. 2013;4(4):453-462. doi:10.3945/an.113.003780. 22. Bener A, Al-Hamaq AOAA, Kurtulus EM, Abdullatef WK, Zirie M. The role of vitamin D, obesity and physical exercise in regulation of glycemia in Type 2 Diabetes Mellitus patients. Diabetes Metab Syndr Clin Res Rev. 2016;10(4):198-204. doi:10.1016/j.dsx. 2016.06.007. 23. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Evaluation, treatment, and prevention of Vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. doi:10.1210/jc.2011-0385. 24. Lips P, Hosking D, Lippuner K, Norquist JM, Wehren l, Maalouf G, Ragi- eis SC. The prevalence of Vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med.

68 http://igusabder.gelisim.edu.tr

B. G. ÇÖL, E. M. KURTULUŞ, F. M. MAJOO

IGUSABDER, 1 (2017): 59-69.

2006;260(3):245-254. doi:10.1111/j.1365-2796.2006.01685.x. 25. Uçar F, Taşlıpınar MY, Soydaş AÖ, Özcan N. Ankara Etlik İhtisas Eğitim ve Araştırma Hastanesine başvuran hastalarda 25-OH Vitamin D düzeyleri. Eur J Basic Med Sci. 2012;2(1):12-15. 26. Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013;5(1):111-148. doi:10.3390/nu5010111. 27. Chin A. Vitamin D-Analyte of the Millennium. EJIFCC. 2011;22(1)(3):1-5. 28. Turkish Ministry of Health. Bebeklerde D Vitamini Yetersizliğinin Önlenmesi ve Kemik Sağlığının Geliştirilmesi Programı. http://cocukergen.thsk.saglik.gov.tr/daire-faaliyetleri/beslenme/752- bebeklerde-d-vitamini-yetersizliğinin-önlenmesi-ve-kemik-sağlığının- geliştirilmesi-programı.html. Accessed February 12, 2017.

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